Substituted Azaquinazolines Having an Antiviral Action

ABSTRACT

This invention relates to substituted azaquinazolines, to a process for their preparation, to pharmaceutical compositions containing them, and to their use for the treatment and/or prophylaxis of diseases, especially for use as antiviral agents, in particular against cytomegaloviruses.

The invention relates to substituted-azaquinazolines and process fortheir preparation, and to their use for producing medicaments for thetreatment and/or prophylaxis of diseases, especially for use asantiviral agents, in particular against cytomegaloviruses.

The synthesis of dihydroquinazolines is described in Saito T., et al.Tetrahedron Lett., 1996, 37, 209-212 and in Wang F., et al. TetrahedronLett., 1997, 38, 8651-8654.

Although agents having antiviral activity and different structures areavailable on the market, the therapies currently available withganciclovir, valganciclovir, foscarnet and cidofovir are associated withsevere side effects, e.g. nephrotoxicity, neutropenia orthrombocytopenia. It is moreover regularly possible for a resistance todevelop. Novel agents for effective therapy are therefore desirable.

One object of the present invention is therefore to provide novelcompounds with identical or improved antiviral effect for the treatmentof viral infectious diseases in humans and animals.

It has surprisingly been found that the substituted azaquinazolinesdescribed in the present invention have antiviral activity.

The invention relates to compounds of the formula

in which

-   Ar is aryl, in which aryl may be substituted by 1 to 3 substituents,    where the substituents are selected independently of one another    from the group consisting of alkyl, alkoxy, formyl, hydroxycarbonyl,    alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano,    hydroxy, amino, alkylamino, aminocarbonyl and nitro,    -   in which alkyl may be substituted by 1 to 3 substituents, where        the substituents are selected independently of one another from        the group consisting of halogen, amino, alkylamino, hydroxy and        aryl,    -   or two of the substituents on the aryl form together with the        carbon atoms to which they are bonded a 1,3-dioxolane, a        cyclopentane ring or a cyclohexane ring, and an optionally        present third substituent is selected independently thereof from        the said group,-   Q¹, Q², Q³ and Q⁴ are CH or N,    -   where one or two of Q¹, Q², Q³ and Q⁴ are N and the others are        simultaneously CH,-   R¹ is hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano,    halogen, nitro or trifluoromethyl,-   R² is hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or    trifluoromethyl,-   R³ is amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen,    nitro, trifluoromethyl, alkyl-sulphonyl or alkylaminosulphonyl,    or    one of the radicals R¹, R² and R³ is hydrogen, alkyl, alkoxy, cyano,    halogen, nitro or trifluoromethyl, and the other two form together    with the carbon atoms to which they are bonded a 1,3-dioxolane, a    cyclopentane ring or a cyclohexane ring,-   R⁴ is hydrogen or alkyl,-   R⁵ is hydrogen or alkyl,    or    the radicals R⁴ and R⁵ in the piperazine ring are bonded to exactly    opposite carbon atoms and form a methylene bridge optionally    substituted by 1 to 2 methyl groups,-   R⁶ is hydrogen, alkyl, alkoxy, alkylthio, formyl, hydroxycarbonyl,    aminocarbonyl, alkyl-carbonyl, alkoxycarbonyl, trifluoromethyl,    halogen, cyano, hydroxy or nitro,    and-   R⁷ is hydrogen, alkyl, alkoxy, alkylthio, formyl, hydroxycarbonyl,    alkylcarbonyl, alkoxy-carbonyl, trifluoromethyl, halogen, cyano,    hydroxy or nitro,    and the salts thereof, the solvates thereof and the solvates of the    salts thereof.

Compounds of the invention are the compounds of the formula (I) and thesalts, solvates and solvates of the salts thereof, compounds mentionedhereinafter as exemplary embodiment(s) and the salts, solvates andsolvates of the salts thereof, where the compounds which are encompassedby formula (I) and are mentioned hereinafter are not already salts,solvates and solvates of the salts.

The compounds of the invention may, depending on their structure, existin stereoisomeric forms (enantiomers, diastereomers). The inventiontherefore relates to the enantiomers or diastereomers and respectivemixtures thereof. The stereoisomerically pure constituents can beisolated in a known manner from such mixtures of enantiomers and/ordiastereomers.

If the compounds of the invention can exist in tautomeric forms, thepresent invention includes all tautomeric forms.

Salts preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds of the invention.However, salts which are not themselves suitable for pharmaceuticalapplications but can be used for example for isolating or purifying thecompounds of the invention are also included.

Physiologically acceptable salts of the compounds of the inventioninclude acid addition salts of mineral acids, carboxylic acids andsulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonicacid, toluene-sulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid,propionic acid, lactic acid, tartaric acid, malic acid, citric acid,fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of the invention alsoinclude salts of usual bases such as, by way of example and preferably,alkali metal salts (e.g. sodium and potassium salts), alkaline earthmetal salts (e.g. calcium and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 C atoms such as,by way of example and preferably, ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine andN-methylpiperidine.

Solvates refer for the purposes of the invention to those forms of thecompounds of the invention which form a complex in the solid or liquidstate by coordination with solvent molecules. Hydrates are a specialform of solvates in which the coordination takes place with water.

For the purposes of the present invention, unless specified otherwise,the substituents have the following meaning:

Alkyl per se and “alk” and “alkyl” in alkoxy, alkylthio, alkylamino,alkylcarbonyl, alkylsulphonyl, alkylaminosulphonyl and alkoxycarbonylare a linear or branched alkyl radical having normally 1 to 6,preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by wayof example and preferably methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

Alkoxy is, by way of example and preferably, methoxy, ethoxy, n-propoxy,isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylthio is, by way of example and preferably, methylthio, ethylthio,n-propylthio, isopropylthio, tert-butylthio, n-pentylthio andn-hexylthio.

Alkylamino is an alkylamino radical having one or two alkyl substituents(chosen independently of one another) by way of example and preferablymethylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propyl-amino, N-tert-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino. C₁-C₃-alkylamino isfor example a monoalkylamino radical having 1 to 3 carbon atoms or adialkylamino radical having in each case 1 to 3 carbon atoms per alkylsubstituent.

Alkylsulphonyl is, by way of example and preferably, methylsulphonyl,ethylsulphonyl, n-propyl-sulphonyl, isopropylsulphonyl,tert-butylsulphonyl, n-pentylsulphonyl and n-hexylsulphonyl.

Alkylaminosulphonyl is an alkylaminosulphonyl radical having one or twoalkyl substitutents (chosen independently of one another), by way ofexample and preferably, methylaminosulphonyl, ethylaminosulphonyl,n-propylaminosulphonyl, isopropylaminosulphonyl,tert-butylaminosulphonyl, n-pentylaminosulphonyl,n-hexyl-aminosulphonyl, N,N-dimethylaminosulphonyl,N,N-diethyl-aminosulphonyl, N-ethyl-N-methylaminosulphonyl,N-methyl-N-n-propylaminosulphonyl, N-isopropyl-N-n-propylaminosulphonyl,N-tert-butyl-N-methylaminosulphonyl, N-ethyl-N-n-pentylaminosulphonyland N-n-hexyl-N-methylaminosulphonyl. C₁-C₃-Alkylaminosulphonyl is forexample a monoalkyl-aminosulphonyl radical having 1 to 3 carbon atoms ora dialkylaminosulphonyl radical having in each case 1 to 3 carbon atomsper alkyl substituent.

Alkylcarbonyl is, by way of example and preferably, acetyl andpropanoyl.

Alkoxycarbonyl is, by way of example and preferably, methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Aryl is a mono- to tricyclic aromatic carbocyclic radical havingnormally 6 to 14 carbon atoms, by way of example and preferably phenyl,naphthyl and phenanthrenyl.

Halogen is fluorine, chlorine, bromine and iodine, preferably fluorineand chlorine.

A symbol * on a carbon atom means that, in relation to the configurationat this carbon atom, the compound is in enantiopure form, by which ismeant for the purposes of the present invention an enantiomeric excessof more than 90% (>90% ee).

Preference is given to those compounds of the formula (I) in which

-   Ar is phenyl, in which phenyl may be substituted by 1 to 3    substituents, where the substituents are selected independently of    one another from the group consisting of C₁-C₆-alkyl, C₁-C₆-alkoxy,    hydroxycarbonyl, C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl,    trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy, amino,    C₁-C₆-alkylamino and nitro,    -   or two of the substituents on the phenyl form together with the        carbon atoms to which they are bonded a 1,3-dioxolane, and an        optionally present third substituent is selected independently        thereof from the said group,-   Q¹, Q² and Q³ are CH or N,    -   where always exactly one of Q¹, Q² and Q³ is N and the others        are simultaneously CH,-   Q⁴ is CH,-   R¹ is hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, fluorine    or chlorine,-   R² is hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, fluorine    or chlorine,-   R³ is C₁-C₄-alkyl, cyano, fluorine, chlorine, nitro, trifluoromethyl    or C₁-C₃-alkylsulphonyl,    or    one of the radicals R¹, R² and R³ is hydrogen, C₁-C₃-alkyl,    C₁-C₃-alkoxy, cyano, halogen, nitro or trifluoromethyl, and the    other two form together with the carbon atoms to which they are    bonded a cyclopentane ring or a cyclohexane ring,-   R⁴ is hydrogen or methyl,-   R⁵ is hydrogen,-   R⁶ is hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, hydroxycarbonyl,    aminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxy    or nitro,    and-   R⁷ is hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, fluorine, chlorine, cyano    or hydroxy.

Preference is given among these in particular to those compounds of theformula (I) in which

-   Ar is phenyl, in which phenyl may be substituted by 1 to 2    substituents, where the substituents are selected independently of    one another from the group consisting of methyl, methoxy, fluorine    and chlorine,-   Q¹, Q² and Q³ is CH or N,    -   where always exactly one of Q¹, Q² and Q³ is N, and the others        are simultaneously CH,-   Q⁴ is CH,-   R¹ is hydrogen, methyl, methoxy, methylthio, fluorine or chlorine,-   R² is hydrogen,-   R³ is methyl, isopropyl, tert-butyl, cyano, fluorine, chlorine,    nitro or trifluoromethyl,-   R⁴ is hydrogen,-   R⁵ is hydrogen,-   R⁶ is hydrogen, aminocarbonyl, fluorine, chlorine, cyano or hydroxy,    and-   R⁷ is hydrogen.

Preference is given among these very particularly to those compounds ofthe formula (I) in which

-   Ar is phenyl, in which phenyl may be substituted by 1 to 2    substituents, where the substituents are selected independently of    one another from the group consisting of methyl, methoxy, fluorine    and chlorine,-   Q¹, Q² and Q³ are CH or N,    -   where always exactly one of Q¹, Q² and Q³ is N, and the others        are simultaneously CH,-   Q⁴ is CH,-   R¹ is hydrogen, methyl or methoxy,-   R² is hydrogen,-   R³ is methyl, tert-butyl, chlorine or trifluoromethyl,-   R⁴ is hydrogen,-   R⁵ is hydrogen,-   R⁶ is hydrogen    and-   R⁷ is hydrogen.

Preference is also given to those compounds of the formula (I) in whichR¹ is hydrogen, methyl, methoxy or fluorine.

Preference is given among these in particular to those compounds of theformula (I) in which R¹ is methoxy.

Preference is also given to those compounds of the formula (I) in whichR¹ is bonded to the phenyl ring via the position ortho to the point oflinkage of the phenyl ring. The point of linkage of the phenyl ringsubstituted by the radicals R¹, R² and R³ means in the context of thepresent invention that carbon atom of the phenyl ring which is linked toone of the two dihydroquinazoline nitrogen atoms according to formula(I).

Particular preference is given to those compounds of the formula (I) inwhich R¹ is methoxy, and R¹ is bonded to the phenyl ring via theposition ortho to the point of linkage of the phenyl ring.

Preference is also given to those compounds of the formula (I) in whichR² is hydrogen.

Preference is also given to those compounds of the formula (I) in whichR³ is trifluoromethyl, chlorine, methyl, isopropyl or tert-butyl.

Preference is given among these in particular to those compounds of theformula (I) in which R³ is trifluoromethyl, chlorine or methyl.

Preference is given among these very particularly to those compounds ofthe formula (I) in which R³ is trifluoromethyl.

Preference is also given to those compounds of the formula (I) in whichR¹ is bonded to the phenyl ring via the position ortho to the point oflinkage of the phenyl ring, and R³ is bonded to the phenyl ring via theposition opposite to R¹ and meta to the point of linkage of the phenylring.

Particular preference is given to those compounds of the formula (I) inwhich R¹ is bonded to the phenyl ring via the position ortho to thepoint of linkage of the phenyl ring, R³ is trifluoromethyl, chlorine ormethyl, and R³ is bonded to the phenyl ring via the position opposite toR¹ and meta to the point of linkage of the phenyl ring.

Particular preference is given among these to those compounds of theformula (I) in which R¹ is bonded to the phenyl ring via the positionortho to the point of linkage of the phenyl ring, R³ is trifluoromethyl,and R³ is bonded to the phenyl ring via the position opposite to R¹ andmeta to the point of linkage of the phenyl ring.

Preference is also given to those compounds of the formula (I) in whichR⁴ and R⁵ are hydrogen.

Preference is also given to those compounds of the formula (I) in whichR⁶ is hydrogen.

Preference is also given to those compounds of the formula (I) in whichR⁷ is hydrogen.

Preference is also given to those compounds of the formula (I) in whichAr is phenyl, in which phenyl may be substituted by 1 to 2 substituents,where the substituents are selected independently of one another fromthe group consisting of methyl, methoxy and fluorine and chlorine.

The definitions of radicals indicated specifically in the respectivecombinations or preferred combinations of radicals are replacedirrespective of the particular combinations indicated for the radicalsas desired also by definitions of radicals of another combination.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

The invention further relates to a process for preparing compounds ofthe formula (I), where compounds of the formula

in whichAr, Q¹, Q², Q³, Q⁴, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have the meaningindicated above, andR⁸ is alkyl, preferably methyl or ethyl, or tert-butyl,are reacted with bases or acids.

The reaction in the case of methyl and ethyl generally takes place withbases in inert solvents, preferably in a temperature range from roomtemperature to reflux of the solvents under atmospheric pressure.

Examples of bases are alkali metal hydroxides such as sodium, lithium orpotassium hydroxide, or alkali metal carbonates such as caesiumcarbonate, sodium or potassium carbonate, where appropriate in aqueoussolution, with preference for sodium hydroxide in water.

Examples of inert solvents are ethers such as 1,2-dimethoxyethane,dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldimethyl ether, alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol or tert-butanol, or mixtures of solvents, withpreference for dioxane or tetrahydrofuran.

In the case of tert-butyl, the reaction generally takes place with acidsin inert solvents, preferably in a temperature range from 0° C. to 40°C. under atmospheric pressure.

Acids suitable in this connection are hydrogen chloride in dioxane,hydrogen bromide in acetic acid or trifluoroacetic acid in methylenechloride.

The compounds of the formula (II) are known or can be prepared byreacting compounds of the formula

in whichQ¹, Q², Q³, Q⁴, R⁶, R⁷ and R⁸ have the meaning indicated above,in a two-stage reaction firstly with compounds of the formula

in whichR¹, R² and R³ have the meaning indicated above,and subsequently with compounds of the formula

in whichAr, R⁴ and R⁵ have the meaning indicated above.

The reaction takes place in both stages generally in inert solvents,preferably in a temperature range from room temperature to 100° C. underatmospheric pressure. Silica gel is added where appropriate to thereaction mixture in the second stage. The reaction preferably takesplace with a working up between the first and second stage.

Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, hydrocarbons such as benzene, xylene, toluene, hexane,cyclohexane or petroleum fractions, or other solvents such asdimethylformamide, dimethylacetamide, acetonitrile or ethyl acetate, ormixtures of solvents, with preference for methylene chloride.

The compounds of the formula (IV) are known or can be synthesized byknown processes from appropriate precursors.

The compounds of the formula (V) are known or can be synthesized byknown processes from appropriate precursors, for example by aBuchwald-Hartwig reaction in accordance with the following synthesisscheme (review in: C. G. Frost, P. Mendonca, J. Chem. Soc., Perkin TransI, 1998, 2615-2623):

Buchwald-Hartwig reaction:

The precursors required for this are known or can be synthesized byknown processes from appropriate precursors.

The compounds of the formula (III) are known or can be prepared byreacting compounds of the formula

in whichQ¹, Q², Q³, Q⁴, R⁶, R⁷ and R⁸ have the meaning indicated above,with triphenylphosphine and tetrachloromethane.

The reaction generally takes place in inert solvents in the presence ofa base, preferably in a temperature range from room temperature to 50°C. under atmospheric pressure.

Examples of inert solvents are ethers such as diethyl ether, methyltert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycoldimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such asbenzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, orother solvents such as dimethylformamide, dimethylacetamide,acetonitrile or pyridine, with preference for acetonitrile.

Examples of bases are alkali metal and alkaline earth metal carbonatessuch as caesium carbonate, sodium or potassium carbonate or amines suchas triethylamine, diisopropylethylamine, N-methyl-morpholine orpyridine, with preference for triethylamine.

The compounds of the formula (VI) are known or can be synthesized byknown processes from appropriate precursors, for example by a Heckreaction or a Wittig-Horner reaction according to the followingsynthesis schemes:

Heck Reaction:

Wittig-Horner Reaction:

The precursors required for this are known or can be synthesized byknown processes from appropriate precursors.

Preparation of the compounds of the invention can be illustrated by thefollowing synthesis scheme.

Synthesis Scheme:

The compounds of the invention of the formula (I) show a surprisingrange of effects which could not have been predicted. They show anantiviral effect on representatives of the group of Herpes viridae(herpes viruses), in particular on cytomegaloviruses (CMV) especially onhuman cytomegalovirus (HCMV).

Areas of indication which may be mentioned by way of example are:

-   1) Treatment and prophylaxis of HCMV infections in AIDS patients    (retinitis, pneumonitis, gastrointestinal infections).-   2) Treatment and prophylaxis of cytomegalovirus infections in    bone-marrow and organ transplant patients who develop often    life-threatening HCMV pneumonitis or encephalitis, and    gastrointestinal and systemic HCMV infections.-   3) Treatment and prophylaxis of HCMV infections in neonates and    infants.-   4) Treatment of an acute HCMV infection in pregnant women.-   5) Treatment of HCMV infection in immunosuppressed patients    associated with cancer and cancer therapy.-   6) Treatment of HCMV-positive cancer patients with the aim of    reducing HCMV-mediated tumour progression (cf. J. Cinati, et al.,    FEMS Microbiology Reviews 2004, 28, 59-77).

The present invention further relates to the use of the compounds of theinvention for the treatment and/or prophylaxis of diseases, inparticular of infections with viruses, especially the aforementionedviruses, and of the infectious diseases caused thereby. A viralinfection means hereinafter both an infection with a virus and a diseasecaused by an infection with a virus.

The invention further relates to the use of the compounds of theinvention for the treatment and/or prophylaxis of disorders, especiallyof the aforementioned disorders.

The present invention further relates to the use of the compounds of theinvention for producing a medicament for the treatment and/orprophylaxis of disorders, especially the aforementioned disorders.

The compounds of the invention are preferably used to producemedicaments which are suitable for the prophylaxis and/or treatment ofinfections with a representative of the group of Herpes viridae,particularly a cytomegalovirus, in particular human cytomegalovirus.

The present invention further relates to a method for the treatmentand/or prophylaxis of disorders, especially the aforementioneddisorders, by using an antivirally effective amount of the compounds ofthe invention.

The present invention further relates to medicaments comprising at leastone compound of the invention and at least one or more further activeingredients, in particular for the treatment and/or prophylaxis of theaforementioned disorders. Suitable active ingredients in the combinationwhich may be mentioned by way of example and preferably are: antiviralactive ingredients such as gancyclovir or acyclovir.

The compounds of the invention may have systemic and/or local effects.They can for this purpose be administered in a suitable way, such as,for example, by the oral, parenteral, pulmonary, nasal, sublingual,lingual, buccal, rectal, dermal, transdermal, conjunctival, otic ortopical route, or as implant or stent.

For these administration routes it is possible to administer thecompounds of the invention in suitable administration forms.

Suitable for oral administration are administration forms which functionaccording to the prior art and deliver the compounds of the inventionrapidly and/or in modified manner and which comprise the compounds ofthe invention in crystalline and/or amorphicized and/or dissolved form,such as, for example, tablets (uncoated or coated tablets, for examplewith coatings which are resistant to gastric juice or dissolve with adelay or are insoluble and control the release of the compound of theinvention), tablets which disintegrate rapidly in the oral cavity, orfilms/wafers, films/lyophilisates, capsules (for example hard or softgelatin capsules), sugar-coated tablets, granules, pellets, powders,emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (e.g. intravenous, intraarterial, intracardiac, intraspinal orintralumbar) or with inclusion of absorption (e.g. intramuscular,subcutaneous, intracutaneous, percutaneous, or intraperitoneal).Administration forms suitable for parenteral administration are, interalia, preparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilisates or sterile powders.

Examples suitable for the other administration routes are pharmaceuticalforms for inhalation (inter alia powder inhalers, nebulizers), nasaldrops, solutions, sprays; tablets, films/wafers or capsules, to beadministered lingually, sublingually or buccally, suppositories,preparations for the eyes and ears, vaginal capsules, aqueoussuspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems, milk, pastes, foams,dusting powders, implants or stents.

The compounds of the invention can be converted into the statedadministration forms. This can take place in a manner known per se bymixing with inert, non-toxic, pharmaceutically suitable excipients.These include, inter alia, carriers (for example microcrystallinecellulose, lactose, mannitol), solvents (for example liquid polyethyleneglycols), emulsifiers and dispersants or wetting agents (for examplesodium dodecyl sulphate, polyoxysorbitan oleate), binders (for examplepolyvinylpyrrolidone), synthetic and natural polymers (for examplealbumin), stabilizers (for example antioxidants such as ascorbic acid),colours (for example inorganic pigments such as iron oxides) or flavour-and/or odour-masking agents.

The present invention further relates to medicaments which comprise atleast one compound of the invention, usually together with one or moreinert, non-toxic, pharmaceutically suitable excipients, and to the usethereof for the aforementioned purposes.

It has generally proved advantageous to administer on intravenousadministration amounts of about 0.001 to 10 mg/kg, preferably about 0.01to 5 mg/kg, of body weight to achieve effective results, and the dosageon oral administration is about 0.01 to 25 mg/kg, preferably 0.1 to 10mg/kg, of body weight.

It may nevertheless be necessary where appropriate to deviate from theamounts mentioned, specifically as a function of the body weight,administration route, individual response to the active ingredient, modeof preparation and time or interval over which administration takesplace. Thus, it may be sufficient in some cases to make do with lessthan the aforementioned minimum amount, whereas in other cases the upperlimit mentioned must be exceeded. It may in the event of administrationof larger amounts be advisable to divide these into a plurality ofindividual doses over the day.

The percentage data in the following tests and examples are percentagesby weight unless otherwise indicated; parts are parts by weight. Solventratios, dilution ratios and concentration data of liquid/liquidsolutions are in each case based on volume.

A. EXAMPLES Abbreviations

-   BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl-   ca. circa-   CDCl₃ deuterochloroform-   conc. concentrated-   DCI direct chemical ionization (in MS)-   DCM dichloromethane-   DIEA N,N-diisopropylethylamine-   DMSO dimethylsulphoxide-   DMF N,N-dimethylformamide-   EE ethyl acetate (acetic acid ethyl ester)-   EI electron impact ionization (in MS)-   ESI electrospray ionization (in MS)-   h hour-   HPLC high pressure, high performance liquid chromatography-   LC-MS coupled liquid chromatography-mass spectroscopy-   LDA lithium diisopropylamide-   Min minutes-   m.p. melting point-   MS mass spectroscopy-   MTBE Methyl tert-butyl ether-   NMR nuclear magnetic resonance spectroscopy-   Pd—C palladium on carbon-   RP-HPLC reverse phase HPLC-   RT room temperature-   R_(t) retention time (in HPLC)-   sat. saturated-   THF tetrahydrofuran-   TLC thin layer chromatography

General LC-MS and HPLC Methods:

Method 1 (analytical HPLC): Instrument: HP 1100 with DAD detection;column: Kromasil RP-18, 60 mm×2 mm, 3.5 μm; eluent A: 5 ml HClO4/1water, eluent B: acetonitrile; gradient: 0 min 2% B, 0.5 min 2% B, 4.5min 90% B, 6.5 min 90% B; flow rate: 0.75 ml/min; oven: 30° C.; UVdetection: 210 nm.

Method 2 (preparative HPLC, laboratory HPLC): Column: CromSil C18, 250mm×30 mm; flow rate: 50 ml/min; running time: 38 min; eluent A: water,eluent B: acetonitrile, gradient 10% B (3 min)→90% B (31 min)→90% B (34min)→10% B (34.01 min): UV detection: 210 nm.

Method 3 (LCMS): Instrument: Micromass Quattro LCZ, with HPLC Agilentseries 1100; column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; eluent A:1 l of water+1 ml of 50% formic acid, eluent B: 1 l of acetonitrile+1 mlof 50% formic acid; gradient: 0.0 min 100% A→0.2 min 100% A →2.9 min 30%A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate: 0.8 ml/min; UVdetection: 208-400 nm.

Starting Compounds Example 1A Pyridin-4-yl tert-butyl carbamate

2.0 g (21.3 mmol) of 4-aminopyridine are added in portions to a solutionof 5.1 g (23.4 mmol) of di-tert-butyl dicarbonate in 20 ml of THF. Afterthe addition is complete, the mixture is stirred at room temperature for1 h, then the solvent is removed in vacuo, and the residue obtained inthis way is suspended in diethyl ether. The solid is filtered off anddried in vacuo. Yield: 3.43 g (83% of theory).

HPLC (method 1): R_(t)=3.42 min

MS (ESI-pos): m/z=195 [M+H]⁺

Example 2A Pyridin-3-yl tert-butyl carbamate

18.2 g (40.9 mmol) of lead(IV) acetate are added to a solution of 5.0 g(40.9 mmol) of nicotinamide in 100 ml of tert-butanol, and the reactionmixture is stirred under reflux for 4 h. The mixture is then filteredthrough kieselguhr, the solvent is removed in vacuo, and the residue istaken up in diethyl ether. The organic phase is washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution,dried over sodium sulphate and filtered. The solution is mixed withpentane, and the resulting precipitate is filtered off and dried. Yield:2.79 g (35% of theory).

HPLC (Method 1): R_(t)=3.36 min

MS (ESI-pos): m/z=195 [M+H]⁺

Example 3A (3-Formylpyridin-4-yl) tert-butyl carbamate

4.12 g (21.3 mmol) of the Boc-protected aminopyridine from Example 1Aare dissolved in 75 ml of tetrahydrofuran, the solution is cooled to−78° C. under argon, and 34 ml of a 1.5M solution (51.1 mmol) oftert-butyllithium in pentane are added dropwise. The addition takesplace so that the internal temperature remains below −65° C. After theaddition is complete, the mixture is stirred at −20° C. for 1 h. Then10.6 ml (138.3 mmol) of absolute N,N-dimethylformamide are added to themixture so that the reaction temperature remains below −15° C. duringthe addition. The reaction is stirred at room temperature for 16 h andthen, while cooling in ice, 1N hydrochloric acid is added. The pH isadjusted to pH 7 with solid sodium carbonate, ethyl acetate is added tothe mixture, and the organic phase is washed with water and saturatedsodium chloride solution. The organic phase is separated off and driedover sodium sulphate, and the solvent is removed in vacuo. The productis purified by chromatography on silica gel with cyclohexane/ethylacetate (3:2 v/v). 3.15 g (63% of theory) of product are obtained.

HPLC (method 1): R_(t)=3.65 min

MS (ESI-pos): m/z=223 [M+H]⁺

Example 4A (4-Formylpyridin-3-yl) tert-butyl carbamate

2.7 g (13.9 mmol) of the Boc-protected aminopyridine from Example 2A aredissolved in 50 ml of tetrahydrofuran, the solution is cooled to −78° C.under argon, and 22.4 ml of a 1.5 M solution (33.4 mmol) oftert-butyllithium in pentane are added dropwise. The addition takesplace so that the internal temperature remains below −65° C. After theaddition is complete, the mixture is stirred at −20° C. for 1 h. Then4.6 ml (41.7 mmol) of N-formylpiperidine are added to the mixture sothat the reaction temperature remains below −15° C. during the addition.The reaction is stirred at room temperature for 16 h and then, whilecooling in ice, 1N hydrochloric acid is added. The pH is adjusted to pH7 with solid sodium carbonate, ethyl acetate is added to the mixture,and the organic phase is washed with water and saturated sodium chloridesolution. The organic phase is separated off and dried over sodiumsulphate, and the solvent is removed in vacuo. The product is purifiedby chromatography on silica gel with cyclohexane/ethyl acetate (7:3v/v). 1.54 g (49% of theory) of product are obtained.

HPLC (method 1): R_(t)=3.40 min

MS (ESI-pos): m/z=223 [M+H]⁺

Example 5A 3-Amino-2-bromopyridine

4.00 g (42.5 mmol) of 3-aminopyridine are dissolved in 200 ml ofacetonitrile and, after addition of 8.32 g (46.8 mmol) ofN-bromosuccinimide, stirred at room temperature with exclusion of lightfor 20 h. The reaction mixture is then concentrated, suspended in ethylacetate and washed with saturated aqueous sodium bicarbonate solutionand saturated aqueous sodium chloride solution. The organic phase isdried over sodium sulphate, filtered and concentrated. Purification isby column chromatography on silica gel with cyclohexane/ethyl acetate(1:1). 969 mg (12% of theory) of product are obtained.

HPLC (method 1): R_(t)=1.08 min.

MS (ESI-pos): m/z=173 [M+H]⁺

Example 6A tert-Butyl (2E)-3-(3-aminopyridin-2-yl)acrylate

950 mg (4.94 mmol) of the bromide from Example 5A, 1900 mg (14.83 mmol)of tert-butyl acrylate, 330 mg (1.50 mmol) of palladium(II) acetate, 450mg (1.50 mmol) of tri-ortho-tolylphospine are dissolved in 15 ml ofacetonitrile, and 1000 mg (9.88 mmol) of triethylamine are added. Themixture is stirred under reflux for 16 h. The reaction mixture isconcentrated, mixed with ethyl acetate and washed with saturated aqueoussodium chloride solution. The organic phase is dried over sodiumsulphate, filtered, concentrated and purified by column chromatographyon silica gel with cyclohexane/ethyl acetate (7:3). 95 mg (6% of theory)of product are obtained.

Example 7A Methyl(2E)-3-{4-[(tert-butoxycarbonyl)amino]pyridin-3-yl}acrylate

A suspension of 3.0 g (13.5 mmol) of the aldehyde from Example 3A, 3.12g (14.8 mmol) of methyl diethyl phosphonoacetate and 623 mg (14.8 mmol)of lithiumhydroxidemonohydrate in 30 ml of tetrahydrofuran is stirred atroom temperature for 16 h. This is followed by addition of 30 ml ofwater and extraction with ethyl acetate. The organic phase is separatedoff, washed with saturated sodium chloride solution, dried over sodiumsulphate and filtered, and the solvent is removed in vacuo. The residueis dried at 100° C./1 mbar. 3.5 g (89% of theory) of the title compoundwere obtained.

HPLC (method 1): R_(t)=3.71 min

MS (ESI-pos): m/z=279 [M+H]⁺

Example 8A Methyl(2E)-3-{3-[(tert-butoxycarbonyl)amino]pyridin-4-yl}acrylate

A suspension of 1.48 g (6.66 mmol) of the aldehyde from Example 4A, 1.54g (7.33 mmol) of methyl diethyl phosphonoacetate and 307 mg (7.33 mmol)of lithiumhydroxidemonohydrate in 15 ml of tetrahydrofuran is stirred atroom temperature for 16 h. This is followed by addition of 15 ml ofwater and extraction with ethyl acetate. The organic phase is separatedoff, washed with saturated sodium chloride solution, dried over sodiumsulphate and filtered, and the solvent is removed in vacuo. The residueis dried at 75° C./1 mbar. 1.82 g (98% of theory) of the title compoundare obtained.

HPLC (method 1): R_(t)=3.73 min

MS (ESI-pos): m/z=279 [M+H]⁺

Example 9A Methyl (2E)-3-{4-aminopyridin-3-yl}acrylate

900 mg (3.23 mmol) of the Boc-protected aminopyridine from Example 7Aare dissolved in 3 ml of trifluoroacetic acid at 0° C. The reactionmixture is then stirred at room temperature for 1 h, the mixture isintroduced into ice-cold sodium bicarbonate solution and stirred for 30min, and the resulting precipitate is filtered off, washed with waterand dried. 242 mg (42% of theory) of the title compound are obtained.

A further 105 mg (18% of theory) of product can be isolated as an oilfrom the mother liquor by adjusting the pH to pH 10 and extraction withethyl acetate. The two fractions presumably differ in their degree ofprotonation.

HPLC (method 1): R_(t)=2.67 min

MS (CI-pos): m/z=179 [M+H]⁺

Example 10A Methyl (2E)-3-{3-aminopyridin-4-yl}acrylate

1.8 g (6.47 mmol) of the Boc-protected aminopyridine from Example 8A aredissolved in 18 ml of methanol at room temperature, and 1 ml ofconcentrated hydrochloric acid is added to the solution. The reactionmixture is then stirred at 70° C. for 4 h, the mixture is introducedinto 50 ml of sodium bicarbonate solution, the pH is adjusted to pH 14by adding 20% strength sodium hydroxide solution, and the mixture isextracted with ethyl acetate. The organic phase is washed withconcentrated sodium chloride solution and dried over sodium sulphate,and the solvent is removed in vacuo. Yield: 935 mg (79% of theory).

HPLC (method 1): R_(t)=2.88 min

MS (ESI-pos): m/z=179 [M+H]⁺

General Procedure [A]: Preparation of Iminophosphoranes fromAminopyridines

1.0 eq. of aminopyridine, 2.0 eq. of triphenylphosphine, 10.0 eq. oftetrachloromethane and 10.0 eq. of triethylamine are suspended inacetonitrile (ca. 0.33 M based on the aminopyridine). The reactionmixture is stirred at room temperature for 16 h, and the solvent isremoved in vacuo. The crude product is reacted without furtherpurification or is purified by column chromatography on silica gel.

Example 11A tert-Butyl(2E)-3-{3-[(triphenylphosphoranylidene)amino]pyridin-2-yl}acrylate

Starting from 95 mg (0.28 mmol) of aminopyridine from Example 6A,general procedure [A] results in the crude product which is purified bycolumn chromatography on silica gel with cyclohexane/ethyl acetate(7:3). 70 mg (51% of theory) of product are obtained.

HPLC (method 1): R_(t)=4.83 min.

MS (ESI-pos): m/z=481 [M+H]⁺

Example 12A Methyl(2E)-3-{4-[(triphenylphosphoranylidene)amino]pyridin-3-yl}acrylate

Starting from 320 mg (1.8 mmol) of aminopyridine from Example 9A,general procedure [A] results in 1650 mg of crude product which isreacted without further purification.

Example 13A Methyl(2E)-3-{3-[(triphenylphosphoranylidene)amino]pyridin-4-yl}acrylate

Starting from 900 mg (4.89 mmol) of aminopyridine from Example 10A,general procedure [A] results in 1910 mg of crude product which isreacted without further purification.

MS (ESI-pos): m/z=439 [M+H]⁺

General Procedure [B]: Preparation of Carbodiimides fromIminophosphoranes by Reaction with Isocyanates

1.0 eq. of iminophosphorane (where appropriate as crude product) isdissolved in dichloromethane, 1.1 eq. of isocyanate are added, and thereaction mixture is stirred at room temperature for 16 h. The crudeproduct obtained in this way is directly reacted further.

Example 14A tert-Butyl(2E)-3-{3-[({[3-(trifluoromethyl)phenyl]imino}methylene)amino]pyridin-2-yl}acrylate

65 mg (0.14 mmol) of iminophosphorane from Example 11A are reacted bygeneral procedure [B] with 27 mg (0.14 mmol) of 3-trifluoromethylphenylisocyanate, and the crude product is reacted further withoutpurification.

Example 15A Methyl(2E)-3-{4-[({[3-(trifluoromethyl)phenyl]imino}methylene)amino]pyridin-3-yl}acrylate

300 mg (0.34 mmol) of iminophosphorane from Example 12A are reacted bygeneral procedure [B] with 70 mg (0.38 mmol) of 3-trifluoromethylphenylisocyanate, and the crude product is reacted further withoutpurification.

Example 16A Methyl(2E)-3-[4-({[(2-methoxy-5-methylphenyl)imino]methylene}amino)pyridin-3-yl]acrylate

150 mg (0.28 mmol) of iminophosphorane from Example 12A are reacted bygeneral procedure [B] with 67 mg (0.42 mmol) of 1-methoxy-4-methylphenylisocyanate, and the crude product is reacted further withoutpurification.

Example 17A Methyl(2E)-3-{3-[({[3-(trifluoromethyl)phenyl]imino}methylene)amino]pyridin-4-yl}acrylate

1000 mg (1.37 mmol) of aminopyridine from Example 13A are reacted bygeneral procedure [B] with 282 mg (1.51 mmol) of 3-trifluoromethylphenylisocyanate, and the crude product is reacted further withoutpurification.

Example 18A Methyl(2E)-3-{4-[({[2-methoxy-5-(trifluoromethyl)phenyl]imino}methylene)amino]pyridin-3-yl}acrylate

1017 mg (1.90 mmol) of iminophosphorane from Example 12A are reacted bygeneral procedure [B] with 413 mg (1.90 mmol) of1-methoxy-4-trifluoromethylphenyl isocyanate, and the crude product isreacted further without purification.

Example 19A 2-Isocyanato-1-methoxy-4-(trifluoromethyl)benzene

3 g (15.69 mmol) of 2-methoxy-5-trifluoromethylaniline are dissolved in100 ml of dichloromethane, and 6.73 g (31.39 mmol) of1,8-bis(dimethylamino)naphthalene are added. At 0-5° C., 2.24 g (11.3mmol) of trichloromethyl chloroformate, dissolved in 50 ml ofdichloromethane, are added dropwise, and the mixture is stirred at 0° C.for 30 min and at room temperature for 60 min. It is washed at 0° C.with 1N hydrochloric acid, ice-water and sodium bicarbonate solution.The product is obtained after drying over magnesium sulphate and removalof the solvent by distillation. The isocyanate is then reacted withoutfurther purification in the following reactions. Yield: 3 g (88% oftheory)

General Procedure [C]: Reaction of Carbodiimides with Phenylpiperazinesto Give Dihydropyridopyrimidinylacetic Esters

1.0 eq of carbodiimide (where appropriate as crude product) is dissolvedin dichloromethane, 1.05 eq of phenylpiperazine and a spatula tip ofsilica gel are added, and the reaction mixture is stirred under refluxfor 16 h. The solvent is then removed in vacuo, and the product ispurified by chromatography on silica gel or by preparative HPLC (method2).

Example 20A Methyl{2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido-[3,4-d]pyrimidin-4-yl}acetate

Starting from 250 mg (0.34 mmol) of the carbodiimide from 17 A and 65 mg(0.36 mmol) of 4-fluorophenylpiperazine, general procedure [C] andpurification twice by preparative HPLC result in 64 mg (33% of theory)of product.

HPLC (method 1): R_(t)=4.42 min

MS (ESI-pos): m/z=528 [M+H]⁺

Example 21A Methyl{2-[4-(3-methylphenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido-[3,4-d]pyrimidin-4-yl}acetate

Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17Aand 63 mg (0.36 mmol) of 3-methylphenylpiperazine, general procedure [C]and purification by preparative HPLC result in 88 mg (48% of theory) ofproduct.

HPLC (method 1): R_(t)=4.42 min

MS (ESI-pos): m/z=524 [M+H]⁺

Example 22A Methyl{2-[4-(3-chlorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido-[3,4-d]pyrimidin-4-yl}acetate

Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17Aand 71 mg (0.36 mmol) of 3-chlorophenylpiperazine, general procedure [C]and purification by preparative HPLC result in 102 mg (53% of theory) ofproduct.

HPLC (method 1): R_(t)=4.65 min

MS (ESI-pos): m/z=544 [M+H]⁺

Example 23A Methyl{2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido-[3,4-d]pyrimidin-4-yl}acetate

Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17Aand 69 mg (0.36 mmol) of 3-methoxyphenylpiperazine, general procedure[C] and purification by preparative HPLC result in 90 mg (46% of theory)of product.

HPLC (method 1): R_(t)=4.40 min

MS (ESI-pos): m/z=540 [M+H]⁺

Example 24A Methyl{2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido-[4,3-d]pyrimidin-4-yl}acetate

Starting from 107 mg (0.31 mmol) of the carbodiimide from Example 15Aand 56 mg (0.31 mmol) of 4-fluorophenylpiperazine, general procedure [C]and purification by preparative HPLC result in 50 mg (28% of theory) ofproduct.

HPLC (method 1): R_(t)=4.60 min

MS (ESI-pos): m/z=528 [M+H]⁺

Example 25A Methyl{2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido-[4,3-d]pyrimidin-4-yl}acetate

Starting from 107 mg (0.31 mmol) of the carbodiimide from Example ISAand 59 mg (0.31 mmol) of 3-methoxyphenylpiperazine, general procedure[C] and purification by preparative HPLC result in 40 mg (23% of theory)of product.

HPLC (method 1): R_(t)=4.60 min

MS (ESI-pos): m/z=540 [M+H]⁺

Example 26A tert-Butyl{2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido-[3,2-d]pyrimidin-4-yl}acetate

Starting from 53 mg (0.14 mmol) of the carbodiimide from Example 14A and24 mg (0.14 mmol) of 4-fluorophenylpiperazine, general procedure [C] andpurification on preparative HPLC result in 38 mg (48% of theory) ofproduct.

HPLC (method 1): R_(t)=4.87 min

MS (ESI-pos): m/z=570 [M+H]⁺

Example 27A Methyl[2-[4-(4-fluorophenyl)piperazin-1-yl]-3-(2-methoxy-5-methylphenyl)-3,4-dihydropyrido-[4,3-d]pyrimidin-4-yl]acetate

Starting from 91 mg (0.28 mmol) of the carbodiimide from Example 16A and76 mg (0.42 mmol) of 4-fluorophenylpiperazine, general procedure [C] andpurification by preparative HPLC result in 14 mg (9% of theory) ofproduct.

HPLC (method 1): R_(t)=4.23 min

MS (ESI-pos): m/z=504 [M+H]⁺

Example 28A Methyl{2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl}acetate

Starting from 565 mg (1.50 mmol) of the carbodiimide from Example 18Aand 297 mg (1.65 mmol) of 4-fluorophenylpiperazine, general procedure[C] and purification by preparative

HPLC result in 90 mg (10% of theory) of product.

HPLC (method 1): R_(t)=4.44 min

MS (ESI-pos): m/z=558 [M+H]⁺

Exemplary Embodiments General Procedure [D] Ester Hydrolysis

1.0 equivalent of the ester is dissolved in dioxane (ca. 0.5 Msolution), then 3.0 equivalents of 1N sodium hydroxide solution areadded, and the reaction mixture is stirred at 50° C. for 16 h. Themixture is then adjusted to pH 5 with 1N hydrochloric acid, the solventis removed in vacuo, and the product is purified by chromatography onsilica gel or preparative HPLC.

Example 1{2-[4-(4-Fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido[3,4-d]-pyrimidin-4-yl}aceticacid hydrochloride

Starting from 44 mg (0.08 mmol) of the ester from Example 20A, reactionby general procedure [D] and purification by preparative HPLC result in24 mg (52% of theory) of product.

HPLC (method 1): R_(t)=4.19 min

MS (ESI-pos): m/z=514 [M+H—HCl]⁺

¹H-NMR (400 MHz, CD₃CN+DMSO-d₆): δ [ppm]=8.34 (s, 1H); 8.11 (d, 1H);7.62 (s, 1H); 7.47 (t, 1H); 7.39-7.37 (m, 2H); 7.07 (t, 1H); 6.99 (t,1H); 6.91-6.87 (m, 1H); 5.27-5.23 (m, 1H); 3.58-3.53 (m, 2H), furtherprotons underneath the solvent or water signal.

Example 2{2-[4-(3-Methylphenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido[3,4-d]-pyrimidin-4-yl}aceticacid hydrochloride

Starting from 70 mg (0.13 mmol) of the ester from Example 21A, reactionby general procedure [D] and purification by preparative HPLC result in51 mg (71% of theory) of product.

HPLC (method 1): R_(t)=4.21 min

MS (ESI-pos): m/z=510 [M+H—HCl]⁺

¹H-NMR (400 MHz, CD₃CN+DMSO-d₆): δ [ppm]=8.34 (s, 1H); 8.12 (d, 1H);7.62 (s, 1H); 7.44 (t, 1H); 7.38-7.36 (m, 2H); 7.10 (t, 1H); 7.05 (d,1H); 6.89-6.88 (m, 1H); 6.72-6.64 (m, 3H); 5.26-5.22 (m, 1H); 3.59-3.53(m, 2H); 3.08-2.95 (m, 3H); 2.72-2.65 (m, 1H); 2.48-2.46 (m, 1H); 2.25(s, 3H).

Example 3{2-[4-(3-Chlorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido[3,4-d]-pyrimidin-4-yl}aceticacid hydrochloride

Starting from 84 mg (0.15 mmol) of the ester from Example 22A. reactionby general procedure [D] and purification by preparative HPLC result in44 mg (52% of theory) of product.

HPLC (method 1): R_(t)=4.43 min.

MS (ESI-pos): m/z=530 [M+H—HCl]⁺

¹H-NMR (400 MHz, CD₃CN+DMSO-d₆): δ [ppm]=8.34 (s, 1H); 8.12 (d, 1H);7.62 (s, 1H); 7.46 (t, 1H); 7.39-7.35 (m, 2H); 7.19 (t, 1H); 7.05 (d,1H); 6.89-6.88 (m, 1H); 6.83-6.79 (m, 2H); 5.26-5.22 (m, 1H); 3.59-3.53(m, 2H); 3.13-3.02 (m, 3H); 2.72-2.65 (m, 1H); 2.48-2.41 (m, 1H).

Example 4{2-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido[3,4-d]-pyrimidin-4-yl}aceticacid hydrochloride

Starting from 72 mg (0.13 mmol) of the ester from Example 23A, reactionby general procedure [D] and purification by preparative HPLC result in48 mg (67% of theory) of product.

HPLC (method 1): R_(t)=4.18 min.

MS (ESI-pos): m/z=526 [M+H—HCl]⁺

¹H-NMR (400 MHz, CD₃CN+DMSO-d₆): δ [ppm]=8.35 (s, 1H); 8.12 (d, 1H);7.56 (s, 1H); 7.46 (t, 1H); 7.39-7.36 (m, 2H); 7.12 (t, 1H); 7.05 (d,1H); 6.50-6.47 (m, 1H); 6.43-6.39 (m, 2H); 5.26-5.22 (m, 1H); 3.73 (s,3H); 3.59-3.52 (m, 2H); 3.09-2.98 (m, 3H); 2.72-2.65 (m, 1H); 2.48-2.46(m, 1H).

Example 5{2-[4-(4-Fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido[4,3-d]-pyrimidin-4-yl}aceticacid hydrochloride

Starting from 38 mg (0.07 mmol) of the ester from Example 24A, reactionby general procedure [D] and purification by preparative HPLC result in24 mg (67% of theory) of product.

HPLC (method 1): R_(t)=4.24 min.

MS (ESI-pos): m/z=514 [M+H—HCl]⁺

¹H-NMR (400 MHz, CD₃CN): δ [ppm]=8.22 (d, 1H); 8.18 (s, 1H); 7.45 (s,1H); 7.40-7.36 (m, 3H); 7.03-6.83 (m, 5H); 5.28 (t, 1H); 3.603-3.50 (m,4H); 2.99-2.90 (m, 4H); 2.78 (dd, 1H); 2.57 (dd, 1H).

Example 6{2-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido[4,3-d]-pyrimidin-4-yl}aceticacid

Starting from 27 mg (0.05 mmol) of the ester from Example 25A, reactionby general procedure [D] and purification by preparative HPLC result in19 mg (72% of theory) of product.

HPLC (method 1): R_(t)=4.24 min.

MS (ESI-pos): m/z=526 [M+H—HCl]⁺

¹H-NMR (400 MHz, CD₃CN): δ [ppm]=8.24 (d, 1H); 8.18 (s, 1H); 7.45 (s,1H); 7.40-7.35 (m, 3H); 7.12 (t, 1H); 7.01 (d, 1H); 6.45 (d, 1H);6.41-6.38 (m, 2H); 5.28 (t, 1H); 3.72 (s, 3H); 3.60-3.54 (m, 4H);3.07-2.78 (m, 4H); 2.55 (dd, 2H).

Example 7{2-[4-(4-Fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrido[3,2-d]-pyrimidin-4-yl}aceticacid hydrochloride

Starting from 25 mg (0.04 mmol) of the ester from Example 26A, reactionby general procedure [D] and purification by preparative HPLC result in16 mg (66% of theory) of product.

HPLC (method 1): R_(t)=4.30 min.

MS (ESI-pos): m/z=514 [M+H—HCl]⁺

¹H-NMR (400 MHz, CD₃CN): δ [ppm]=8.12 (d, 1H); 7.60 (s, 1H); 7.45-7.39(m, 4H); 7.22 (dd, 1H); 6.96 (t, 2H); 6.89-6.86 (m, 2H); 5.18 (dd, 1H);3.68-3.59 (m, 4H); 3.06-2.99 (m, 4H); 2.76 (dd, 1H); 2.63 (dd, 1H).

Example 8[2-[4-(4-Fluorophenyl)piperazin-1-yl]-3-(2-methoxy-5-methylphenyl)-3,4-dihydropyrido[4,3-d]-pyrimidin-4-yl}aceticacid

Starting from 12 mg (0.02 mmol) of the ester from Example 27A, reactionby general procedure [D] and purification by preparative HPLC result in11 mg (97% of theory) of product.

HPLC (method 1): R_(t)=4.05 min.

MS (ESI-pos): m/z=490 [M+H]⁺

¹H-NMR (400 MHz, CD₃CN): δ [ppm]=8.14-8.10 (m, 2H); 7.15-6.81 (m, 8H);4.86-4.84 (m, 1H); 3.77-3.73 (m, 4H); 3.50 (s, 3H); 2.96-2.92 (m, 2H);2.78-2.74 (m, 2H); 2.49 (dd, 1H); 2.50-2.48 (m, 1H, partly underneathCH₃ signal); 2.44 (s, 3H).

Example 9{2-[4-(4-Fluorophenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-pyrido[4,3-d]pyrimidin-4-yl}aceticacid

Starting from 80 mg (0.14 mmol) of the ester from Example 28A, reactionby general procedure [D] and purification by preparative HPLC result in27 mg (35% of theory) of product.

HPLC (method 3): R_(t)=2.31 min.

MS (ESI-pos): m/z=543 [M+H]⁺

¹H-NMR (400 MHz, CD₃CN): δ [ppm]=8.26-8.20 (m, 2H); 7.55 (d, 1H); 7.16(d, 1H); 7.10-6.78 (m, 6H); 5.00 (dd, 1H); 3.88-3.80 (m, 4H); 3.54 (s,3H); 3.03 (dd, 1H); 2.96-2.91 (m, 2H); 2.79-2.77 (m, 2H); 2.55 (dd, 1H).

B. ASSESSMENT OF THE PHYSIOLOGICAL ACTIVITY

The in vitro effect of the compounds of the invention can be shown inthe following assays:

Anti-HCMV (Anti-Human Cytomegalovirus) Cytopathogenicity Tests

The test compounds are employed as 50 millimolar (mM) solutions indimethyl sulphoxide (DMSO). Ganciclovir®, Foscarnet® and Cidofovir® areused as reference compounds. After addition of in each case 2 μl of the50, 5, 0.5 and 0.05 mM DMSO stock solutions to 98 μl portions of cellculture medium in row 2 A-H for duplicate determinations, 1:2 dilutionsare carried out with 50 μl portions of medium up to row 11 of the96-well plate. The wells in rows 1 and 12 each contain 50 μl of medium.150 μl of a suspension of 1×10⁴ cells (human prepuce fibroblasts [NHDF])are then pipetted into each of the wells (row 1=cell control) and, inrows 2-12, a mixture of HCMV-infected and uninfected NHDF cells(M.O.I.=0.001−0.002), i.e. 1-2 infected cells per 1000 uninfected cells.Row 12 (without substance) serves as virus control. The final testconcentrations are 250-0.0005 μM. The plates are incubated at 37° C./5%CO₂ for 6 days, i.e. until all the cells are infected in the viruscontrols (100% cytopathogenic effect [CPE]). The wells are then fixedand stained by adding a mixture of formalin and Giemsa's dye (30minutes), washed with double-distilled water and dried in a drying ovenat 50° C. The plates are then assessed visually using an overheadmicroscope (plaque multiplier from Technomara).

The following data can be acquired from the test plates:

CC₅₀ (NHDF)=substance concentration in μM at which no visible cytostaticeffects on the cells are evident by comparison with the untreated cellcontrol;EC₅₀ (HCMV)=substance concentration in μM which inhibits the CPE(cytopathic effect) by 50% compared with the untreated virus control;SI (selectivity index)=CC₅₀ (NHDF)/EC₅₀ (HCMV).

Representative in vitro data for the effects of the compounds of theinvention are shown in Table A:

TABLE A Example NHDF CC₅₀ HCMV EC₅₀ SI No. [μM] [μM] HCMV 4 94 0.2 470 8250 0.14 1786 9 94 0.05 1880

The suitability of the compounds of the invention for the treatment ofHCMV infections can be shown in the following animal model:

HCMV Xenograft Gelfoam® Model Animals:

3-4-week old female immunodeficient mice (16-18 g), Fox Chase SCID orFox Chase SCID-NOD or SCID beige, are purchased from commercial breeders(Taconic M+B, Jackson, USA). The animals are housed under sterileconditions (including bedding and feed) in isolators.

Virus Growing:

Human cytomegalovirus (HCMV), Davis or AD169 strain, is grown in vitroon human embryonic prepuce fibroblasts (NHDF cells). After the NHDFcells have been infected with a multiplicity of infection (M.O.I.) of0.01-0.03, the virus-infected cells are harvested 5-10 days later andstored in the presence of minimal essential medium (MEM), 10% foetalcalf serum (FCS) with 10% DMSO at −40° C. After serial ten-folddilutions of the virus-infected cells, the titer is determined on24-well plates of confluent NHDF cells after vital staining with neutralred.

Preparation of the Sponges, Transplantation, Treatment and Evaluation:

Collagen sponges 1×1×1 cm in size (Gelfoam®; from Peasel & Lorey, orderNo. 407534; K. T. Chong et al., Abstracts of 39^(th) InterscienceConference on Antimicrobial Agents and Chemotherapy, 1999, p. 439) areinitially wetted with phosphate-buffered saline (PBS), the trapped airbubbles are removed by degassing, and then stored in MEM+10% FCS. 1×10⁶virus-infected NHDF cells (infection with HCMV Davis or HCMV AD169M.O.I.=0.03) are detached 3 hours after infection and added in a drop of20 μl of MEM, 10% FCS, to a moist sponge. About 16 hours later, theinfected sponges are incubated with 25 μl of PBS/0.1% BSA/1 mM DTT with5 ng/μl basic fibroblast growth factor (bFGF). For the transplantation,the immunodeficient mice are anesthetized with Avertin or aketamine/xylazine/azepromazine mixture, the fur on the back is removedusing a shaver, the epidermis is opened 1-2 cm, unstressed and the moistsponges are transplanted under the dorsal skin. The surgical wound isclosed with tissue glue. 6 hours after the transplantation, the mice canbe treated for the first time (one treatment is given on the day of theoperation). On subsequent days, oral treatment with the substance iscarried out three times a day (7.00 h and 14.00 h and 19.00 h), twice aday (8 h and 18 h) or once a day (14 h) over a period of 8 days. Thedaily dose is for example 3 or 10 or 30 or 60 or 100 mg/kg of bodyweight, the volume administered is 10 ml/kg of body weight. Thesubstances are formulated in the form of a 0.5% strength Tylosesuspension with 2% DMSO or a 0.5% strength Tylose suspension. 9 daysafter transplantation and 16 hours after the last administration ofsubstance, the animals are painlessly sacrificed and the sponge isremoved. The virus-infected cells are released from the sponge bycollagenase digestion (330 U/1.5 ml) and stored in the presence of MEM,10% foetal calf serum, 10% DMSO at −140° C. Evaluation takes place afterserial ten-fold dilutions of the virus-infected cells by determining thetiter on 24-well plates of confluent NHDF cells after vital stainingwith neutral red. The number of infected cells or infectious virusparticles (infectious center assay) after the substance treatmentcompared with the placebo-treated control group is determined.

CYP Inhibition Assay

To investigate the mechanism-based (irreversible) inhibition of CYP3A4,the test substance is incubated in various concentrations with humanliver microsomes (2 mg/ml microsomal protein) in potassium phosphatebuffer of pH 7.4 with the addition of NADPH-generating system (NADP⁺,glucose 6-phosphate and glucose-6-phosphate dehydrogenase) at 37° C. 2aliquots are removed from the incubation at various times.

The first aliquot is incubated 1:50 in a new incubation solution(phosphate buffer, NADPH-generating system and 10 μM midazolam) at 37°C. for a further 10 min. The incubation is then stopped withacetonitrile on ice, the protein is pelleted in a centrifuge at 15 000g, and the supernatant is analysed by standard methods of HPLC/MS forthe formation of 1′-hydroxymidazolam.

The second aliquot is stopped with acetonitrile on ice and analysed byHPLC/UV/MS for remaining test substances.

Parameters typical of irreversible inhibition (k_(inact), K_(i) andpartition ratio r) are determined from the two analytical data sets, andthe test substance is assessed therewith (cf A. Madan, et al., in A. D.Rodrigues (ed.) “Drug-Drug Interaction” in “Drugs and the PharmaceuticalScience”, Vol. 116, ISBN 0-8247-0283.2, Marcel Dekker Inc., New York,2002.).

C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted into pharmaceuticalpreparations in the following ways:

Tablet: Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50mg of corn starch (native), 10 mg of polyvinylpyrolidone (PVP 25) (fromBASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of active ingredient, lactose and starch is granulated witha 5% strength solution (m/m) of the PVP in water. The granules are thendried and mixed with the magnesium stearate for 5 min. This mixture iscompressed using a conventional tablet press (see above for format ofthe tablet). A guideline for the compressive force used for thecompression is 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum from FMC, Pa., USA) and 99 g of water.

10 ml of oral suspension are equivalent to a single dose of 100 mg ofthe compound of the invention.

Production:

The Rhodigel is suspended in ethanol, and the active ingredient is addedto the suspension. The water is added while stirring. The mixture isstirred for about 6 h until the swelling of the Rhodigel is complete.

Solution which can be Administered Intravenously:

Composition:

10-500 mg of the compound of Example 1, 15 g of polyethylene glycol 400and 250 g of water for injections.

Production:

The compound of Example 1 is dissolved together with polyethylene glycol400 in the water with stirring. The solution is sterilized by filtration(pore diameter 0.22 μm) and dispensed under aseptic conditions intoheat-sterilized infusion bottles. The latter are closed with infusionstoppers and crimped caps.

1. A compound of the formula

in which Ar is aryl, in which aryl may be substituted by 1 to 3substituents, where the substituents are selected independently of oneanother from the group consisting of alkyl, alkoxy, formyl,hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl,halogen, cyano, hydroxy, amino, alkylamino, aminocarbonyl and nitro, inwhich alkyl may be substituted by 1 to 3 substituents, where thesubstituents are selected independently of one another from the groupconsisting of halogen, amino, alkylamino, hydroxy and aryl, or two ofthe substituents on the aryl form together with the carbon atoms towhich they are bonded a 1,3-dioxolane, a cyclopentane ring or acyclohexane ring, and an optionally present third substituent isselected independently thereof from the said group, Q¹, Q², Q³ and Q⁴are CH or N. where one or two of Q¹, Q², Q³ and Q⁴ are N and the othersare simultaneously CH, R¹ is hydrogen, amino, alkyl, alkoxy, alkylamino,alkylthio, cyano, halogen, nitro or trifluoromethyl, R² is hydrogen,alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl, R³is amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro,trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl, or one of theradicals R¹, R² and R³ is hydrogen, alkyl, alkoxy, cyano, halogen, nitroor trifluoromethyl, and the other two form together with the carbonatoms to which they are bonded a 1,3-dioxolane, a cyclopentane ring or acyclohexane ring, R⁴ is hydrogen or alkyl, R⁵ is hydrogen or alkyl, orthe radicals R⁴ and R⁵ in the piperazine ring are bonded to exactlyopposite carbon atoms and form a methylene bridge optionally substitutedby 1 to 2 methyl groups, R⁶ is hydrogen, alkyl, alkoxy, alkylthio,formyl, hydroxycarbonyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl,trifluoromethyl, halogen, cyano, hydroxy or nitro, and R⁷ is hydrogen,alkyl, alkoxy, alkylthio, formyl, hydroxycarbonyl, alkylcarbonyl,alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy or nitro, or asalt, solvate, or solvate of a salt thereof.
 2. The compound accordingto claim 1, characterized in that Ar is phenyl, in which phenyl may besubstituted by 1 to 3 substituents, where the substituents are selectedindependently of one another from the group consisting of C₁-C₆-alkyl,C₁-C₆-alkoxy, hydroxycarbonyl, C₁-C₆-alkylcarbonyl,C₁-C₆-alkoxycarbonyl, trifluoromethyl, fluorine, chlorine, bromine,cyano, hydroxy, amino, C₁-C₆-alkylamino and nitro, or two of thesubstituents on the phenyl form together with the carbon atoms to whichthey are bonded a 1,3-dioxolane, and an optionally present thirdsubstituent is selected independently thereof from the said group, Q¹,Q² and Q³ are CH or N, where always exactly one of Q¹, Q² and Q³ is Nand the others are simultaneously CH, Q⁴ is CH, R¹ is hydrogen,C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, fluorine or chlorine, R² ishydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, fluorine orchlorine, R³ is C₁-C₄-alkyl, cyano, fluorine, chlorine, nitro,trifluoromethyl or C₁-C₃-alkylsulphonyl, or one of the radicals R¹, R²and R³ is hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, cyano, halogen, nitro ortrifluoromethyl, and the other two form together with the carbon atomsto which they are bonded a cyclopentane ring or a cyclohexane ring, R⁴is hydrogen or methyl, R⁵ is hydrogen, R⁶ is hydrogen, C₁-C₃-alkyl,C₁-C₃-alkoxy, hydroxycarbonyl, aminocarbonyl, trifluoromethyl, fluorine,chlorine, cyano, hydroxy or nitro, and R⁷ is hydrogen, C₁-C₃-alkyl,C₁-C₃-alkoxy, fluorine, chlorine, cyano or hydroxy.
 3. The compoundaccording to claim 1 or 2, characterized in that Ar is phenyl, in whichphenyl may be substituted by 1 to 2 substituents, where the substituentsare selected independently of one another from the group consisting ofmethyl, methoxy, fluorine and chlorine, Q¹, Q² and Q³ are CH or N, wherealways exactly one of Q¹, Q² and Q³ is N, and the others aresimultaneously CH, Q⁴ is CH, R¹ is hydrogen, methyl or methoxy,methylthio, fluorine or chlorine, R² is hydrogen, R³ is methyl,isopropyl, tert-butyl, cyano, fluorine chlorine, nitro ortrifluoromethyl, R⁴ is hydrogen, R⁵ is hydrogen, R⁶ is hydrogen,aminocarbonyl, fluorine, chlorine, cyano or hydroxy, and R⁷ is hydrogen.4. The compound according to claim 1 or 2, characterized in that Ar isphenyl, in which phenyl may be substituted by 1 to 2 substituents, wherethe substituents are selected independently of one another from thegroup consisting of methyl, methoxy, fluorine and chlorine, Q¹, Q² andQ³ are CH or N, where always exactly one of Q¹, Q² and Q³ is N, and theothers are simultaneously CH, Q⁴ is CH, R¹ is hydrogen, methyl ormethoxy, R² is hydrogen, R³ is methyl, tert-butyl, chlorine ortrifluoromethyl, R⁴ is hydrogen, R⁵ is hydrogen, R⁶ is hydrogen and R⁷is hydrogen.
 5. A process for preparing a compound of the formula (I)according to claim 1, characterized in that a compound of the formula

in which Ar, Q¹, Q², Q³, Q⁴, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have themeanings indicated in claim 1, and R⁸ is alkyl, is reacted with a baseor an acid.
 6. (canceled)
 7. A pharmaceutical composition comprising acompound according to any of claims 1 to 4 in combination with an inert,non-toxic, pharmaceutically suitable excipient.
 8. (canceled) 9.(canceled)
 10. (canceled)
 11. A method for controlling viral infectionsin humans or animals by administering an antivirally effective amount ofat least one compound according to any of claims 1 to 4, or of apharmaceutical composition according to claim
 7. 12. The method of claim11 wherein the viral infection is an infection with humancytomegalovirus (HCMV) or another representative of the group of Herpesviridae.
 13. The process according to claim 5, wherein R⁸ is methyl,ethyl, or tert-butyl.